Good afternoon, and thank you for joining us at the Jefferies New York Global Healthcare Conference. My name is Davis Gramza with the healthcare investment banking team. It is my great pleasure to introduce Nathan Dowden, President and Chief Operating Officer of Entrada Therapeutics.
Thank you very much. Thank you for the introduction, and thank you to the whole Jefferies team for having us at the conference. You guys always put on a really great event. As introed, Nate Dowden, President and Chief Operating Officer of Entrada Therapeutics. What I'm going to do is take you through a quick presentation to introduce the company, to talk a little bit about our science, to talk a little bit about our clinical data. From there, I think Josh and I will probably sit down and just talk a little bit about the company, and he probably has a few questions, some of which might be on your mind. Hopefully I get the presentation moving forward, backward. Thank you. First, a quick disclaimer. Entrada Therapeutics is a publicly traded company since 2021, forward-looking statements. Next slide, please.
I'll start very broad and high level. Entrada Therapeutics today, in 2026, is going through the process of transformation from what was a preclinical company to now a very, very active clinical stage company. At a high level, we have a very deep pipeline. We have five clinical stage programs today led by our ENTR-601-44 and ENTR-601-45 programs that will ultimately be followed by 50 and 51 programs, and that's all in Duchenne muscular dystrophy. We also have our VX-670 DM1 program, which is partnered with Vertex Pharmaceuticals. We have four clinical data catalysts this year in 2026 alone, one of which I'll talk about for just a couple of minutes. We had our first cohort of our ENTR-601-44 clinical data readout recently, and we're very excited about that data.
Following that, I'll go through it in more detail in just a minute, we'll have additional catalysts for that program, for our ENTR-601-45 program, and Vertex has also announced that they plan on a VX-670 data readout in the second half of this year. In addition to all of those clinical programs, we also have two development candidates, one of which we've disclosed, ENTR-801, in an inherited retinal disease called Usher syndrome, and we'll be declaring another candidate very shortly, a little bit later this year, also in an inherited retinal disease. Not only an increasingly deep pipeline, but also an increasing breadth of pipeline across multiple therapeutic categories. Our programs are all differentiated in very significant ways. In the past, we've talked a lot about our highly differentiated preclinical data, whether it's our DMD programs, our DM1 program, or the new IRD programs.
That preclinical data really is best in class. We also now, I'll talk about our clinical data, have very favorable safety data and some really intriguing, we think, clinical data in DMD. All of our molecules are both proprietary and highly differentiated. Both our EEVs, our Endosomal Escape Vehicles, which is the small cyclic peptide that we use to gain cell entry, as well as the name implies, extraordinarily high levels of endosomal escape, and thus allowing for very high levels of target engagement within the cell. Also, the active moieties that we use are also novel and proprietary, all the sequences are extraordinarily potent. We have an FDA Accelerated Approval strategy that we're working through, we're running a number of the clinical trials ex U.S. at this point in time.
Everything that we've done has been informed by input from the agency when it comes to protocol design, and we're running placebo-controlled studies, which we think is very important. We plan on collecting this data together once we finish the multi-ascending dose, open label, and expansion cohorts in our clinical trials for submission. Finally, when we think about the marketplaces that we're working in, even though these are rare disease markets, collectively across the portfolio, it's actually a very significant economic opportunity. Speaking of economics, we're well capitalized to realize a lot of the clinical readouts that I just mentioned. We have cash runway into the third quarter of 2027. In addition, what's probably not appreciated is the partnership that we have with Vertex also has very significant economic milestones still to come should that program progress and be successful.
When the deal was struck, it was up to $485 million in clinical and commercial milestones, and then there are royalties on top of that. Next slide, please. I've talked a little bit about the clinical catalyst, but I'll just go into a little bit more detail, and I'll focus here on ENTR-601-44 program and the ENTR-601-45 program. Starting with ENTR-601-44, we've already read out in the first cohort the Multiple Ascending Dose clinical data, and I'll talk about that in some more detail. As that program goes, by the end of the year, we'll also be reading out open-label data from that clinical trial, where we'll be looking at safety, and we'll also be looking at functional benefit in those patients, and I'll talk about that in just a sec. That's a very exciting, very important data set to come.
We also are then already enrolling and dosing our cohort 2 patients, where we have moved from 6 mg per kilogram in cohort 1 to 12 mg per kilogram in cohort 2, and that data should read out around the end of the year as well. That's 601-44. With respect to 601-45, we'll be reading out the first cohort of 601-45 at 5 mg per kilogram midyear, is what we've guided to. Going forward, we just recently announced this week that we've been given clearance to start dosing a second cohort of patients at 10 mg per kilogram. Hopefully, as we move forward, we will continue not only to see excellent data, but dose-dependent responses. Then, as I mentioned, following those, there'll be the 50 and 51 programs. Next slide, please. This is just an illustration of the pipeline. Next slide, please.
All right, let's go through the cohort one clinical data. First, I'll give you the highlights. First and foremost, this clinical trial is set up to look for safety, and that's obviously what's most important and in everybody's mind as you begin to dose patients. We were very, very pleased to see that the safety profile of this drug is, the easiest way to say it, is unremarkable, which means it looks very, very good, at least at the dose level that we've been looking at. We had no SAEs. Any of the treatment emergent adverse events were mild to moderate. The most frequent one was headache.
Perhaps most importantly, we saw no movement in the renal biomarkers, which is something that folks have asked us about over many years, given the experience that some other peptide-based conjugates have had in the past, and I'll show you that data in just a second. From an efficacy perspective, we got a very early signal and a functional measure called time to rise. This is a very simple functional measure. The children sit on the floor, and they're asked to stand up as fast as they can. It's videotaped. It's under GCP conditions. It is actually quite a rigorous test. We saw the majority of the treated patients actually show an improvement in time to rise over a very short time period. Remember, these patients only got three doses of drug.
We think that's quite exciting, and I'll talk about that in just a sec. This was statistically significant data, both in terms of time to rise as well as a measure called time to rise velocity, which I'll explain in just a sec. This measure, as well as other functional measures such as four-stair climb, stride velocity, 10-meter walk/run, are things that we'll be looking for in the open label period, and that we'll read out at the end of the year, and we'll also be looking for dose-dependent responses in cohort 2. Dropping to the bottom of the slide. That was a very positive surprise. We did not expect to see this data looking so strong so early on in the clinical trial, but we're excited about it.
What we also did not expect to see were some of the plasma exposures of the drug, which came in a little bit lower than we had initially anticipated. We think because those exposures were a little bit lower, we didn't reach a threshold, at least in the mature myofibers, in the mature muscle, in the mature damaged muscle, necessary to demonstrate high levels of improvement in dystrophin and exon skipping. The question is, well, how did we show these functional benefits if we didn't see extraordinary jumps in dystrophin data? We think one of the explanations or the primary explanation may be because we have an advantage when it comes to getting into the muscle stem cells, which are known as the satellite cells. These cells reside in an highly vascularized niche.
They sort of surround the mature myofibers, the mature muscle, which is why they're called satellite cells, and they're bathed in drug early on. We think it's possible that what we've seen is we've reached and exceeded a threshold in those satellite cells before reaching and exceeding a threshold in the older damaged myofibers, which remember, are also in some of these patients, there's fatty infiltrate, there's fibrosis, et cetera. The nice thing is, with respect to both of the challenges that we've seen, these are testable hypotheses. We can go back and we look preclinically and we can look clinically at what's going on with the satellite cells.
With respect to the lower levels of plasma exposure that we saw, and I'll get to it in just a second, effectively what we think is just everything's right shifted, which is to say, in our second cohort of data, the exposures should look like effectively what we thought we were going to see in the first cohort of data. Next slide, please. This is a high-level overview of trial design, just to put it all in context. First of all, there's Multiple Ascending Dose portion of the trial. This is double blind over 19 weeks. We've read out the first cohort at 6 mg per kilogram. We're dosing the second cohort at 12 mg per kilogram. If we need to, we can go up to as much as 18 mg per kilogram in a third cohort.
Muscle biopsies are taken six weeks after the last dose, so day 127. The patients, when they move from each one of the MAD cohorts, once they're done with that, they all move into an open label six-dose period, wherein both the placebo patients and the originally treated patients all get drug. One of the things we're excited about when it comes to the open label data at the end of the year is we'll have crossover patients coming in from a placebo as well. Remember, all of these patients without drug should be getting much, much worse over time. That should be some really interesting data to look for.
In addition to the MAD and the open label, then we'll also be adding an expansion cohort to the clinical trial, and that's really to basically build the numbers so that you have a large enough safety database that you can compile all of this and then submit to the FDA. Next slide, please. Basic baseline characteristics and demographics. One thing that's not on the slide that I can say is one of the important things about the functional data, in particular, when you're looking at the functional data is not only how old are the children when they enroll in the trial, because age can be a predictor of what their trajectory looks like, but what do their baseline values look like when they come into the trial?
The first time they're asked to stand, how fast can they stand as opposed to how fast can they stand at the end of the trial? What I can say is, in this case, the baseline values were well-matched between the placebo and the treated patients. That is important and not on the slide, but I thought I should add that. All the patients are ambulatory. All the patients were on steroids. We tried to match these two populations as best we could. Next slide, please. Safety, again, here's an illustration of what I was just talking about. No SAEs, no discontinuations. All of the patients that were in the MAD portion of this trial are now being dosed in the OL. That's obviously quite favorable. Next slide, please. This slide in particular for us was the win.
This is the only slide you'll see where we show individual patient data. The reason we can show individual patient data is because you cannot tell who got the placebo and who was treated here. What you're looking at, for people who don't know this data, is these are the critical renal biomarkers that you would otherwise have concerns with if you have a peptide conjugate oligonucleotide. As you can see, within normal range, no excursions. The measure that people have been most concerned about, and that has quite frankly killed two competitive programs over the years, would be that serum magnesium number right there. Again, as you can see, everybody within normal range, no excursions. You can see the filtration rate, the eGFR looks great. Serum creatinine looks great.
We're really, really excited about this data. This, in the context of both being allowed by our data monitoring committee to go to 12 mg per kg, as well as most recently with the 45 program being allowed to go to 10 mg per kg, gives us a lot of confidence that there's a wide therapeutic index to come. Next slide, please. Time to rise and time to rise velocity. I talked about this a little bit. Let's go ahead one more slide, please. Yep. Time to rise velocity is something you would expect to move first when it comes to functional data. This is in the literature, this is what others have shown. That is, in fact, what we've seen move first. You might also expect to see stride velocity and four-stair climb move relatively early.
We didn't take baseline values for those in the first cohort, so that's why we don't have that right now. We do expect to see that in the open label. The fact that time to rise velocity moved first and moved quickly is extraordinarily encouraging. We'll be looking at the rest of this as we go, both over time and dose-dependent. Next slide, please. This is what the data looks like. We need to be careful here, right? This is eight patients, six, two design. Six patients got treatment, two patients were on placebo. That time to rise velocity number is reasonably strong. The minimally clinically important difference, MCID published would be a little over 0.02, and that's a measure of rises per second. Our number was more than three and a half times that. It was 0.09.
It was statistically significant. This is, although early, a very, very strong signal. If we can jump ahead to the next slide, please. What's more important actually is in terms of that time to rise number, as compared with, for instance, a steroid, vamorolone, which was approved on its time to rise. Their number versus placebo was 0.06. Ours is 50% higher than that already. Contextually, it's a very, very strong number. Again, as I mentioned, we didn't see the drug concentration levels we expected to see, we saw more rapid clearance basically at the end of the day than we expected to see. Now, that was because we had based our initial calculations on exposures in adults, both adult monkeys as well as our healthy normal volunteer trial, and it turns out in these pediatric patients it's a little bit lower.
It was about half. Remember what I said, we've now moved from 6 mg per kilogram to 12 mg per kilogram. We saw half the exposure in cohort 1. We've doubled the dose. Basically, if you can move to the next slide, the exposures we expect to see in this next cohort are probably going to be roughly what we expected to see in cohort 1. This is juvenile NHP data now that we've brought in-house. We got this juvenile data just about the same time we actually got the pediatric patient data. As you can see, even if we see a linear increase from the juvenile NHP data in exposures, we should see exon skipping that jumps into the 20% range, which should correlate well with dystrophin.
If we move to our 18 mg per kilogram dose, we should see actually a nonlinear jump in that exon skipping and dystrophin production. The net message is, from a functional perspective, we're seeing very early signs we're excited about that are statistically significant. From a biomarker-based perspective, everything's just right-shifted, and that data should come around the end of the year. Next slide, please. Next slide, please. We talked a little bit about the rationale, let me just go through it one more time because it is important to understand at least the cartoon version. Dystrophin plays two roles, everybody's very familiar with the one role that it plays, which is as a shock absorber in mature muscle to mitigate damage every time you contract that muscle. Right. Without the dystrophin, that damage is not mitigated.
Ultimately, you get membrane rupture and ultimately the cells die and the muscle dies. What's not well appreciated is if you don't have dystrophin in the satellite cells, in these stem cells, they will not divide appropriately. All you'll get are more stem cells. They will not divide asymmetrically. They will not turn into mature muscle. There are two issues with that. Number one, more stem cells, hyperplasia basically, can actually be damaging to mature muscle. Number two, there's no way to regenerate that muscle effectively. When you think about it, if all you're doing is getting to the mature muscle, you're simply shoring up a muscle that's already damaged. It's protective, and that's obviously incredibly important, but you're probably not going to get that much stronger.
If you effectuate true regeneration, especially in a growing child, that's where you should probably see an improvement in strength and function. Again, I put this out there as a testable hypothesis, but we'll have ample chance to test that hypothesis once we see the 45 data, but more importantly, the OL data and the cohort 2 data. If you can just jump ahead one more slide, please. We know based on our preclinical work, and we're continuing to do more preclinical work as well as going back and look at some of the muscle biopsies, that we get into these muscle stem cells very, very effectively. We also know that that's an unusual finding. For instance, antibody-based therapies cannot get into quiescent stem cells because there is no transferrin receptor on that quiescent stem cell.
We know that AAVs, the gene therapy vectors, cannot get into those quiescent muscle stem cells. We think this could be a really important differentiating advantage over time. Next slide, please. That's DMD. That's probably what most people want to hear about, but I'll just cover off on the others quickly. DM1. Next slide, please. As I mentioned before, we have a partnership with Vertex. It's very exciting. We partnered this program when it was preclinical, and they've since taken it forward in a phase I/II SAD MAD study. It's a global study. They've said that that data should read out in the second half of this year. We're very curious to see what that looks like. We have a firewall that we're very careful not to even attempt to breach.
Effectively, you know what I know about what's going on with that study outside of what's on ClinicalTrials.gov, we're excited to see the data. Next slide, please. As far as the rest of the programs go, just touching on Usher syndrome very quickly. The way we looked at our IRDs is very similar to the way we looked at our neuromuscular diseases. We looked for diseases where there was basically no effective standard of care, where the biology, however, was well understood, where we thought we had a competitive advantage based on the sequences we were able to build, and where there was at least some proof of concept in the clinic but where that proof of concept had failed to demonstrate a TI and where we thought we could win.
That's how we landed on Usher, and that's how we landed actually on the to-be-announced-shortly second IRD. There are probably around 15,000 patients in the U.S. and Europe with this disease. It's an exon skipping therapy that we're looking at. The preclinical data looks very, very good, and we expect to be able to dose this IVT very, very infrequently. The doses here will obviously be extraordinarily low because you're going directly into the eye, and you have access to the retina. Next slide, please. That's it. That's basically the summary. Great safety, intriguing functional data, and a right-shifted biomarker story for our DMD programs, effectively. VX-670 reading out later this year, and an expanding pipeline. Thanks very much, and Josh, you probably have a couple of questions.
All right. Just a few questions that I think will be helpful for people watching. In terms of safety, your ELEVATE-44-201 program continues to evidence a strong safety profile. Given that there's some commentary in the landscape around liver tox and safety concerns for other DMD clinical programs, what are your thoughts on the go-forward dosing strategy, and how is your asset differentiated?
Yeah. Yeah, I'm glad you asked that question. What's important to know about the peptide-based oligonucleotide conjugates and the PMO chemistry specifically is your organ of toxicity is really the kidney, not the liver. Liver tox has obviously been an issue for the AAVs. It can be an issue for siRNA, ASOs. It's really the kidney that's been a historical concern when it comes to the PMOs, and specifically the PMO conjugates more than anything else. Part of the reason it's been an issue historically for others is because they've had very short half-life, which effectively means you're putting a lot of drug into the kidney very, very quickly, number one. Number two, you haven't had complete processing of the peptide before it goes to the kidney.
You're putting a large cationic load into the kidney in addition to the PMO, and that results in toxicity in the proximal tubule. What's differentiated from our perspective is when we look at our final metabolite, our final metabolite is almost all PMO. It's over 99% PMO. The peptide itself is completely gone. It's taken up into the cytosol, and it's digested in the cytosol. PMO all by itself is not particularly toxic. I think there have been other studies, NHP studies with the naked PMOs, where they've been able to go up to something like 2 grams per kilogram in NHPs before they were able to show toxicity. The fact that our peptide is completely gone when it gets to the kidney, but you still see this extraordinary muscle exposure, we think is really important.
Great, thank you. The earlier than expected functional benefit that you're seeing is really encouraging. Can you share more thoughts on the disconnect between the dystrophin restoration that you saw and the functional benefit, and what additional evidence do you plan to pursue to help evidence your findings?
Yeah. Like I said, we were surprised on both sides of the coin. We were surprised by the exposure and the low dystrophin levels, but we were surprised by the functional data as well. We think it probably comes down to this concept of threshold effect. When you look across the DMD landscape, and you look at the dystrophin levels that folks have posted and the functional data that people have looked at, it's very, very difficult to draw any correlations. One of our competitors put 25% improvement in dystrophin up there and functional data that's very encouraging but doesn't look any better than ours at all, despite the fact that we put 2.5% dystrophin.
If we look at another competitor, they put about 3% dystrophin out there, and they were able to show statistical significance in a functional benefit, and they're now in a phase III trial with that. I think there's a lot more to be learned about the biology here, but we do think that this satellite cell, this muscle stem cell story may be an advantage, and that's why we're going back and we're looking at some more pre-clinical work. We're going back and we're going to look at those biopsies to see if there's something that we can tease out there. Now, we need new clinical assays. Those assays will get validated. It might take a little time to go get that data. If nothing else, it would be extraordinary.
Absolutely. As Entrada continues to progress in the clinic, how has your thinking around market positioning evolved given the number of other competitive programs out there and various approaches to treatment?
Yeah. It's funny, when we started working on DMD, there was nothing for these patients or very, very little for these patients. In the 6.5 years I've been at Entrada, it's become a crowded field, and that's good for the patients. There's never been historically a better time to have more hope if you're a patient or a family. We do think to get to the end game, we do think that ultimately this will become a polypharmacy field, and that's a good thing, right? Because there are a lot of complementary mechanisms out there. In terms of positioning our programs vis-à-vis other exon-skipping programs, because ultimately this is a dystrophy, and ultimately you want to be able to provide these patients with as normal as possible a level of dystrophin.
What it's going to come down to are what it always comes down to in the neuromuscular field, which is, and quite frankly almost any field, safety, number one. Benefit risk, number two. Benefit risk as defined by functional data. It's interesting, when we talk to physicians, what they will tell us is, "We don't really care that much about dystrophin. We only care about dystrophin in the context of it should give us some sense that we're going to see a functional benefit at some point, or it allows us to believe in the functional data that you're showing us. They don't treat dystrophin, they treat function. They want to see these kids get better. They would be happy to see these kids not get worse any faster. Right?
From a positioning perspective, once we get through this Accelerated Approval Program, which what you just need for that is you need a statistically significant improvement in dystrophin, and you need a trend towards functional benefit. You don't need a win on dystrophin. You don't need a win on functional benefit. That's what you need. In your phase III trial and in the marketplace, it's going to come down to functional benefit and safety and then some of the other considerations like dosing every six weeks versus dosing once a week, which is what the current, say, exon 45 skipping therapy is today. That's where we'll be ultimately positioning if the data comes good, as we hope it will.
Great. Thanks. Maybe one last question. Moving beyond the 44 program overall, what level of translation and de-risking should we see between the 44 program and the rest of the franchise, especially 45 program, where you have data expected mid 2026? Is there any potential translation to the Vertex program? Then lastly, how are you thinking about capital formation given the number of upcoming data catalysts that you have on the come?
In terms of translation, safety obviously is fantastic. When you think across programs or you think across if your different program indications, it's what people will always look to is safety. It's the same Endosomal Escape Vehicle across all our programs. All the DMD programs as well as the VX-670 program. The fact that we have the safety data, number one, the fact that we've been allowed by our data monitoring committees to double the dose now in two different drugs, number two, and the fact that obviously Vertex is continuing to move their program forward, so they've had no showstoppers, number three, gives us a lot of confidence across the platform. If we see replicates of this functional data, I think we'll see dose-dependent responses in exon and dystrophin. That's a right shift. We're not super worried about that.
If we see replicates in this functional data across these other catalysts through the rest of the year, obviously that's going to be really exciting for the platform. In the context of capital formation, that should obviously result in significant value accretion for the company. So we have, as I said in the presentation, we have cash through Q3 2027, and so we're well set up to demonstrate our ability to execute against those catalysts. At some point it will make sense to obviously raise more money because those phase III trials are going to be pretty expensive, they're going to be pretty significant, and we're going to be very excited to take them forward.
Of course. Nate, thank you so much for taking the time to present to us today.